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EP-4739660-A1 - CRYSTALLINE TNIK INHIBITOR AND USES THEREOF

EP4739660A1EP 4739660 A1EP4739660 A1EP 4739660A1EP-4739660-A1

Abstract

Described herein are crystalline forms of a TNIK inhibitor of Compound I or salts thereof, as well as pharmaceutical compositions thereof, and methods of use thereof in the treatment of diseases or conditions that would benefit from treatment with Compound I.

Inventors

  • LIANG, Xing
  • WANG, HUI
  • YIN, Yushu

Assignees

  • Insilico Medicine IP Limited

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A crystalline form of Compound I, having a structure of or a pharmaceutically acceptable salt thereof.
  2. The crystalline form of claim 1, wherein the crystalline form is a free base.
  3. The crystalline form of claim 2, wherein the crystalline form is Free Base Pattern A, Free Base Pattern B, Free Base Pattern C, Free Base Pattern D, Free Base Pattern E, Free Base Pattern F, Free Base Pattern G, Free Base Pattern H, Free Base Pattern I, Free Base Pattern J, Free Base Pattern K, or Free Base Pattern L.
  4. The crystalline form of claim 1, wherein the crystalline form is an acetate salt of Compound I, HCl salt of Compound I, or fumarate salt of Compound I.
  5. The crystalline form of claim 4, wherein the crystalline form is HCl salt Pattern A, HCl salt Pattern B, HCl salt Pattern D, fumarate salt Pattern A, or acetate salt Pattern A.
  6. The crystalline form of claim 4, wherein the crystalline form is HCl salt Pattern A.
  7. The crystalline form of claim 4, wherein the crystalline form is HCl salt Pattern B.
  8. The crystalline form of claim 4, wherein the crystalline form is HCl salt Pattern D.
  9. The crystalline form of claim 4, wherein the crystalline form is fumarate salt Pattern A.
  10. The crystalline form of claim 4, wherein the crystalline form is acetate salt Pattern A.
  11. The crystalline form of claim 4, wherein the crystalline form is acetate salt Pattern B.
  12. A solid state form of Compound I, having a structure of or a pharmaceutically acceptable salt thereof, wherein the solid state form is an amorphous form.
  13. A compound, wherein the compound is an acetate salt, HCl salt, or fumarate salt of Compound I, and wherein the Compound I has a structure of
  14. The compound of claim 13, wherein the compound is the acetate salt of Compound I.
  15. The compound of claim 14, wherein the acetate salt of Compound I is formed with acetic acid and Compound I free base in an about 1: 1 molar ratio.
  16. The compound of claim 13, wherein the compound is the HCl salt of Compound I.
  17. The compound of claim 16, wherein the HCl salt of Compound I is formed with HCl and Compound I free base in an about 1: 1 molar ratio.
  18. The compound of claim 16, wherein the HCl salt of Compound I is formed with HCl and Compound I free base in an about 2: 1 molar ratio.
  19. A crystalline form of an acetate salt of 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound I) , wherein the crystalline form is characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 14 as measured using Cu Kα radiation; (b) an XRPD pattern with peaks at 8.7 ±0.2°2-Theta, 14.8 ±0.2°2-Theta, and 20.6 ±0.2°2-Theta, as measured using Cu Kα radiation; (c) an XRPD pattern with three or more peaks at 8.7 ±0.2°2-Theta, 14.8 ±0.2°2-Theta, 17.0 ±0.2°2-Theta, 17.5 ±0.2°2-Theta, 20.6 ±0.2°2-Theta, and 21.6 ±0.2°2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with three or more peaks at 8.7 ±0.2°2-Theta, 14.8 ±0.2°2-Theta, 16.4 ±0.2°2-Theta, 17.0 ±0.2°2-Theta, 17.5 ±0.2°2-Theta, 19.0 ±0.2°2-Theta, 19.7 ±0.2°2-Theta, 20.6 ±0.2°2-Theta, and 21.6 ±0.2°2-Theta as measured using Cu Kα radiation; (e) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 8.7 ±0.2°2-Theta, 13.0 ±0.2°2-Theta, 14.8 ±0.2°2-Theta, 16.4 ±0.2°2-Theta, 17.0 ±0.2°2-Theta, 17.5 ±0.2°2-Theta, 19.0 ±0.2°2-Theta, 19.7 ±0.2°2-Theta, 20.6 ±0.2°2-Theta, 21.6 ±0.2°2-Theta, 25.9 ±0.2°2-Theta, and 28.5 ±0.2°2-Theta as measured using Cu Kα radiation; (f) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in Figure 15; (g) a DSC thermogram with an endothermic peak having an onset temperature at about 159.6 ℃ and/or a peak temperature at about 172.0 ℃; (h) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in Figure 16; (i) a TGA thermogram exhibiting less than about 1%mass loss from the onset of heating up to about 140 ℃; (j) a water uptake of less than 2 %wt between 0%and 95%Relative Humidity (RH) as determined by Dynamic Vapour Sorption (DVS) ; (k) a water uptake of about 1.7%wt between 0%and 95%Relative Humidity (RH) as determined by Dynamic Vapour Sorption (DVS) ; or (l) combinations thereof.
  20. The crystalline form of claim 19, wherein the crystalline form is characterized as exhibiting an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 14 as measured using Cu Kα radiation.

Description

CRYSTALLINE TNIK INHIBITOR AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This international patent application claims the benefit of International Application No. PCT/CN2023/106164, filed July 06, 2023, and International Application No. PCT/CN2024/101076, filed June 24, 2024, each of which is incorporated herein by reference in its entirety. BACKGROUND A biologically active enzyme known as Traf2-and Nck-interacting protein kinase is an enzyme commonly known as the TNIK in humans, and which is encoded by the TNIK gene. TNIK as a serine/threonine kinase is involved in various biological processes. SUMMARY In some aspects, disclosed herein is a crystalline form of Compound I, having a structure of or a pharmaceutically acceptable salt thereof. In some embodiments, the crystalline form is a free base. In some embodiments, the crystalline form is Free Base Pattern A, Free Base Pattern B, Free Base Pattern C, Free Base Pattern D, Free Base Pattern E, Free Base Pattern F, Free Base Pattern G, Free Base Pattern H, Free Base Pattern I, Free Base Pattern J, Free Base Pattern K, or Free Base Pattern L. In some embodiments, the crystalline form is an acetate salt of Compound I, HCl salt of Compound I, or fumarate salt of Compound I. In some embodiments, the crystalline form is HCl salt Pattern A, HCl salt Pattern B, HCl salt Pattern D, fumarate salt Pattern A, or acetate salt Pattern A. In some aspects, disclosed herein is a crystalline form of Free base Pattern J of 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound I) , wherein the crystalline form is characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 47 as measured using Cu Kα radiation; (b) an XRPD pattern with peaks at 8.4 ±0.2 °2-Theta, 14.1 ±0.2 °2-Theta, and 17.7 ±0.2 °2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with three or more peaks at 8.4 ±0.2 °2-Theta, 14.1 ±0.2 °2-Theta, 17.7 ±0.2 °2-Theta, 19.0 ±0.2 °2-Theta, 22.6 ±0.2 °2-Theta, and 25.3 ±0.2 °2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with three or more peaks at 8.4 ±0.2 °2-Theta, 14.1 ±0.2 °2-Theta, 16.0 ±0.2 °2-Theta, 16.8 ±0.2 °2-Theta, 17.7 ±0.2 °2-Theta, 19.0 ±0.2 °2-Theta, 22.6 ±0.2 °2-Theta, 23.1 ±0.2 °2-Theta, 24.3 ±0.2 °2-Theta, and 25.3 ±0.2 °2-Theta as measured using Cu Kα radiation; (e) a Differential Scanning Calorimetry (DSC)  thermogram substantially the same as shown in Figure 48; (f) a DSC thermogram with an endothermic peak having an onset temperature at about 239.8 ℃ and/or a peak temperature at about 241.4 ℃; (g) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in Figure 49; (h) a TGA thermogram exhibiting less than about 1%mass loss from the onset of heating up to about 220 ℃; (i) a water uptake of less than about 1%wt between 0%and 90%Relative Humidity (RH) as determined by Dynamic Vapour Sorption (DVS) ; or (j) combinations thereof. In some aspects, disclosed herein is a pharmaceutical composition comprising the crystalline form of Compound I described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal. In some aspects, disclosed herein is a pharmaceutical composition comprising the crystalline form of Compound I described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated in the form of a solution or suspension pharmaceutical composition for administration to a mammal. In some aspects, described herein is a method of treating or preventing a disease, comprising administering a solid state crystalline form described herein, or a pharmaceutical composition described herein. In any one of the foregoing or related aspects, the disease is a fibrotic disease or condition selected from pulmonary fibrosis, cystic fibrosis, CNS fibrosis, heart fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis, brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Dupytren’s contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, peyronie’s disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis, and adhesive capsulitis fibrosis. In some embodiments, the disease is a fibrotic disease or condition selected from liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc) , and graft-versus-host disease (GVHD) . In some embodiments, the disease is kidney fibrosis. In some embodiments, the disease is skin fibrosis. In some embodiments, the disease is idiopathic pulmonary fibrosis (IPF) . In some embodiments, the disease is associated with TNI